Human cancer viruses establish persistent infections in their hosts. We hypothesize that the risk of viral induced cancer is dependent on early events in virus-host interactions that lead to the establishment of persistent viral infections with elevated viral loads. It is now recognized that polyomavirus SV40 can cause human infections and can be detected in selected human cancers. Early events during SV40 infections in vivo that lead to cancer development have not been explored. This project will utilize the hamster model to identify and characterize virus genetic factors and host responses involved in the pathogenesis of SV40 infections and subsequent carcinogenesis. Specific Aim 1 will identify viral genetic factors that influence patterns of SV40 acute and chronic infections in hamsters. Wild-type SV40 and matched constructs that differ in SV40 strain-specific regions will examine the influence of the regulatory region, the T-antigen variable domain, and SV40 microRNA on establishment of acute and chronic infections in vivo and on viral loads. Specific Aim 2 will define the contribution of viral genetic factors to the development of SV40-mediated malignant disease. Tumor incidences in hamsters exposed to SV40 genetic variants by different routes of administration will be related to the establishment and viral loads of acute and chronic SV40 infections. Early-stage lymphomas will be detected using noninvasive ultrasound and changes in viral expression during tumor progression analyzed. Specific Aim 3 will determine SV40 effects on lymphoid cells and on host responses to infection. The interactions of SV40 with cultured hamster lymphoid cells will be defined with respect to viral expression and cell immortalization. Host responses involving cytokine expression and antibody production will be evaluated in the context of establishment and outcome of virus infections. The potential roles of SV40 microRNA and of cytokine IL-10 in modulating host responses to SV40 infections will be explored. The innovative design of this project will yield significant new understandings of the biology of SV40 infections and of mechanisms relevant to SV40 involvement in human malignancies. New insights into early events in viral pathogenesis will be applicable to polyomavirus infections in humans and may identify novel targets for the development of polyomavirus therapeutics. PUBLIC HEALTH RELEVANCE: Polyomaviruses cause cancer, kidney disease, and neurologic disease. This proposal will identify the interactions of virus genetic factors and host responses that lead to chronic viral infections and subsequent disease development. This project will provide new understandings of mechanisms relevant to polyomaviruses and human cancer and may identify novel targets for therapeutics to treat polyomavirus infections and prevent disease.